Hypertension is a public health problem that affects more than 25% of the adult population worldwide. [1,2] Hypertension has been identified as the leading risk factor for mortality and ranks as the third-leading cause of disability-adjusted life-years. [1,3] Despite the availability of numerous antihypertensive agents, the diagnosis, management, and control of hypertension are far from ideal, with control rates of 6% to 30% in different communities worldwide. [1] Nonadherence to antihypertensive treatment has been associated with lower rates of blood pressure (BP) control and higher rates of cardiovascular events. [4-6] Administration of a once-daily fixed-dose combination (FDC) therapy with >2 classes of antihypertensive agents is a strategy adopted for improving adherence and BP control. This strategy has been described in the recent guidelines, even as an initial therapeutic option. [7,8]
NADPH oxidases have recently been shown to contribute to the pathogenesis of hypertension. See Williams et al., 2007, J. Cardiovasc Pharmacol., 50:9-16 and references therein. It has been suggested that specific inhibitors of these enzymes may have potential therapeutic use in hypertensive disease. Two of the most specific inhibitors, gp91ds-tat and apocynin, have been shown to decrease blood pressure in animal models of hypertension. Other inhibitors, including diphenylene iodonium, aminoethyl benzenesulfono fluoride, S17834, PR39, protein kinase C inhibitors, and VAS2870, have shown promise in vitro, but their in vivo specificity, pharmacokinetics, and effectiveness in hypertension remains to be determined. The currently available antihypertensive agents, angiotensinconverting enyzme inhibitors and angiotensin receptor blockers also effectively inhibit NADPH oxidase activation. Similarly, the cholesterol-lowering agents, statins, have been shown to attenuate NADPH oxidase activation.
Dextromethorphan (DM) is a dextrorotatory morphinan and is widely used as a nonopioid cough suppressant in a variety of over-the-counter remedies. [17] It is an NMDA receptor antagonist. The exact mechanism of action of its antitussive activity, however, remains unclear. Studies using animal models of cerebral ischemia and hypoglycemic neural injuries have demonstrated that DM possesses neuroprotective activity. [18-23] DM effectively inhibited the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced production of reactive oxygen species (ROS). The neuroprotective effect of DM depended on the normal function of NADPH oxidase.[24] Recent in vitro and in vivo studies showed that DM reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice through the direct inhibition of NADPH oxidase and that it also decreases superoxide production in the aorta and carotid artery of apolipoprotein E (apoE)-deficient mice. Liu et al., 2009, Cardiovascular Research, 82:161-169. Alvarez Y et al suggest that the increased production of superoxide anion (O2−) from NADP(H) oxidase in vessels of hypertensive rats contributes to the vasoconstrictor responses and counteracts the increase of NO from iNOS and the consequent modulation of these responses. [25]
Calcium channel blockers (CCBs) are indicated as initial therapy for hypertension. Their benefits and the possible risks have been explored in several clinical trials. [9-14] Use of high-dose CCBs has been associated with a high incidence of adverse events (AEs), such as peripheral edema and constipation. [8,11,12]
Amlodipine is a CCB with antihypertensive properties prescribed as monotherapy. It is one of a series of dihydropyridine calcium antagonists. It has been found to be well tolerated even in high-risk patients, such as those with coronary disease, heart failure, or multiple risk factors for cardiovascular events. [12-16] Amlodipine has a generally slower onset and longer duration of action than, for example, nifedipine. (Jensen, H. et al., J. Hum. Hypertens., 42(S): 541-45, 1990). The metabolites of amlodipine apparently do not possess significant calcium channel blocking activity, while the parent drug offers a biological half-life of some 35-40 hours, prompting a once-daily dosage regimen. (Lorimer, A. R., et al., J. Hum. Hypertens., 3(3): 191-96, 1989; Glasser, S. F. et al., AJH, 2(3): 154-57, 1989). Its ability to block, calcium channels in smooth muscle produces peripheral vasodilation resulting in decreases in both systolic and diastolic blood pressure. The racemic mixture of amlodipine is presently used primarily as an antihypertensive agent, which produces peripheral vasodilation, resulting in decreases in both systolic and diastolic blood pressure when used as an antihypertensive agent. This antihypertensive effect occurs in the relative absence of significant or sustained effects on cardiac rate. However, the administration of the racemic mixture of amlodipine to a human has been found to cause adverse effects, such as edema of the extremities, peripheral edema, headache, flushing/hot flashes, fatigue, vertigo, muscle cramps and dizziness.
There remains a need of novel effective and safe methods and pharmaceutical compositions for treating or preventing hypertension and related symptoms. Such methods and pharmaceutical compositions are described in the present application.